4alpha-methyl-3-oxo-5alpha-steroids and a method for preparation of same



United States Patent 3,057,859 Patented Oct. 9, 1962 3,057,85940L-lVIETHYL-3-0XU-5oc-TER0IDS AND A METHOD FDR PREPARATHON F SAME DavidNeville Kirk and Vladimir Petrow, London, England, assignors to TheBritish Drug Houses Limited No Drawing. Filed June 1, 1960, Ser. No.33,100 Claims priority, application Great Britain June 9, 1959 9 Claims.(Cl. 260239.55)

This invention is for improvements in or relating to organic compounds,and has particular reference to new 4u-methyl-3-oxo-5a-steroids and aprocess for their preparation.

It is an object of the present invention to provide a new process forthe preparation of 4ocmethy13-OXO-5oc steroids and their acylderivatives utilising as starting material a 4-thiomethyl-3-oxo-A-steroid. Very few examples of this group of compounds have beendescribed in the literature, owing to the unsatisfactory methodshitherto available for their preparation. Certain compounds of thistype, however, are of value on account of their biological properties,or as intermediates in the preparation of compounds having valuablebiological properties. Thus, for example,17B-hydroxy-4a-methylandrost-an-3-one and its l7-esters are valuable onaccount of their high anabolic/ androgenic ratios compared withtestosterone and its esters, a property which renders them valuable invarious fields, for example in the veterinary field.

The invention also provides the following new 40:-methyl-3-oxo-5u-steroids which are of value in steroid technology, inthe furtherance of steroidal research and in the application ofsteroidal materials to veterinary and medical practice, whether astablets, elixirs, injections, implants, or other types of pharmaceuticalpreparation well known to those skilled in the art.

(1) 17fi-hydroxy-2uz4a-dimethylandrostan-3-one and its 17-acetoxy andl7-propionoxy derivatives. (2)17fl-hydroxy-4oz:6a-dimethylandrostan-3-one and its 17-acetoxy andl7-propionoxy derivatives. (3)17fl-hydroxy-4a-methyl-19-norandrostan-3-one. (4)20-hydroxy-4a-methyl-5a-pregnan-3-one. (5 4u-methyl-5a-pregnane-3:20-dione. (6) 20-hydroxy-4u: 16a-dimethyl-5u-pregnan-3-one. (7) 4a:16u-dimethyl-5a-pregnane-3 :ZO-dione. (8)1loc-hYdIOXY-4a-II161II1Y1-170cI20:20:21 bismethylenedioxy-5u-pregnan-3-one. (9) 4a-methyl-l7a:20:20:21-bismethylenedioxy 50cpregna-ne-3 1 l-dione. 10) 4zx-rnethyl-5 a 25D-spirostan-B -one. '(11) 20:20-ethy1enedioxy-17a-hydroxy 40c methyl 5ocpregnan-3-one. 12) 17a-hydroxy-4u-methyl-Saregnane-B :ZO-dione. 13)17u-acetoxy-4ot-methyl-5u-pregnane-3 :20-dione.

Compounds 1, 2 and 3 are of value on account of their favourableanabolic/ androgenic ratios, rendering them of utility in producinganabolic effects with minimal androgenie efi'ects.

Compounds 4 and 6 are of value as intermediates for the preparation ofthe corresponding 5a-pregnanedione.

Compounds 5 and 7 are of value on account of their sedative propertiesand as intermediates for the preparation of compounds with sedativeproperties.

Compounds 8 and 9 are intermediates for the preparation of4-methylated-1l-oxygenated derivatives which have antiinflammatoryproperties.

Compound 10 is a general raw material for the preparat'ion of4oc-methyl-androstanolone, a compound of known utility as an anabolic/androgenic agent.

Compounds 11, 12 and 13 are valuable raw materials for the preparationof orally-active progestational agents 2 such for example as4a-methyl-17a-acetoxypregn-l-ene- 3:20-dione.

According to the present invention there is provided a method for thepreparation of 4-Il'l6ti1Yl-3-OXO-5ocsteroids which comprises reacting a4-thiomethyl-3-oxo- A -steroid with a solution of an alkali or alkalineearth metal in liquid ammonia. The sulphur containing group is therebyreductively eliminated and the 4:5-ethylenic structure saturated.

The 4-thiomethyl-3oxo-A -steroids employed as starting materials in thepresent invention are described in our copending application No.852,971, now Patent No. 2,989,552. They may be prepared by condensingthe corresponding 3-oxo-A -steroid with formaldehyde or parafonnaldehydeand a t-hiol in the presence of a basic catalyst. It is not essential toisolate the 4-thiomethyl compounds in crystalline form, as they aregenerally formed in high yield, so that the total product may beemployed for the reaction of the present invention if so desired. a

The metal employed as the reducing agent in this invention may be analkali metal such as lithium, sodium or potassium, or an alkaline earthmetal such as calcium, The preferred metal is lithium. A solution of themetal in liquid ammonia may be brought into contact with a solution ofthe 4-thiomethyl steroid in an inert organic solvent which is preferablytetrahydrofuran, but other inert organic solvents such as ether, dioxanor toluene or mixtures of such solvents may be employed.

The reactants may be brought together in any convenient manner such as,for example, by adding the solution of the steroid in the inert organicsolvent to the solution of the metal in liquid ammonia, or vice versa,or by mixing the steroid solution and the ammonia and allowing theammonia to reflux and dissolve the metal from a Soxhlet or similarextraction vessel, until a blue colour persists in the reaction mixture.The blue colour, due to excess of the metal, is discharged preferably bythe addition of solid ammonium chloride. The product is isolated in anyconvenient way, such as by allowing the ammonia to evaporate andextracting or precipitating the steroid. Possible variations in theseprocedures will be apparent to those skilled in the art.

, The process of the invention is a general one, and may be applied to4-thiomethyl-3-oxo-A -derivatives of androstane, pregnane,sitostane,'ergostane, stigmastane, cholestane and spirostane, and their19-nor and D-homoanalogues.

The following groups do not, in general, interfere with the process ofthe invention:

Hydroxy or alkoxy groups, in particular at positions C11, 17, 20 and 21.

Alkyl groups containing up to five carbon atoms, in particular methylgroups, at positions C l, 2, 6, 7, 9, 11, 14, 16 and 17.

Ketal groups, in particular ethylenedioxy or trimethylenedioxy atpositions C11, 17 and 20, bismethylenedioxy at Cl7a:20:20:2l, anddialkylmethylenedioxy at C16oc117.

'Oxo-g'roups, in particular at positions C11, 17 and 20 do not interferewith the process of the reaction provided that the alkali metal ispresent in excess but they may be reduced by the reagent to thecorresponding 'hydroxy-derivatives, unless they are protected by theforbe apparent to those skilled in the art.

Esterified hydroxyl groups, in particular, at positions C11, 17, 20 and21 do not, in general, interfere with the process of the invention(provided that they are not esterified a-ketols), but hydrolysis of theester group may occur. The resulting hydroxy-compound may bere-converted into an ester by esterification as will be apparent tothose skilled in the art.

Ethylenie linkages not conjugated with the 3-oxo-A system or with otherethylenic linkages or oxo-groups, and in particular isolated ethyleniclinkages at positions C-7:8 and 9:11, will not, in general, interferewith the process of the invention.

In applying the process of the invention to4-thiomethyl-3oxo-N-derivatives additionally substituted byhydroxy-groups, it has been found that isolation of the resulting4:5a-dihydro-4a-methyl-3oxo derivatives is, in general, facilitated byacylation of the total reduction product, isolation therefrom of therequired acyl-derivative, and hydrolysis of the acyl derivative ifdesired to yield the free hydroxy-derivative.

Following is a description, by way of example, of methods of carryingthe invention into effect.

Example 1 4-phenylthiomethyltestosterone g.) in pure dry tetrahydrofuran(100 ml.) was added to a stirred solution of lithium (0.53 g.) inrefluxing liquid ammonia (500 ml.) in a vessel from which atmosphericmoisture was excluded. The mixture was stirred for 2 minutes thentreated with sufficient finely powdered ammonium chloride to dischargethe blue colour. The ammonia was allowed to evaporate, and the residuetreated with water and cholorform. The chloroform layer was washed,dried and evaporated and the residue treated with acetic anhydride ml.)and pyridine (5 ml.) for /2 hour on the steambath, then the mixture wasshaken with water, and the product isolated with ether, which was washedwith water, dilute sulphuric acid, water, sodium hydrogen carbonatesolution, and water until neutral. The ethereal solution was dried andevaporated and the residue purified from methanol to give17B-acetoxy-4a-methylandrostan-3one, M. P. 182 to 184 C., [111 +8 (c.,0.14 in chloroform).

Example 2 Sodium (1.75 g.) was substituted for lithium in Example 1,with similar results.

Example 3 Potassium (3.00 g.) was substituted for lithium in Example 1,with similar results.

Example 4 Calcium (1.72 g.) was substituted for lithium in Example 1,with similar results.

Example 5 2a-methyl-4-phenylthiomethyltestosterone reacted with lithiumin liquid ammonia by the process of Example 1 gave17,8-acetoxy-2a:4a-dimethylandrostan-3-one, needles from methanol, M.P.170 to 171 C., [(11 +17 (c., 0.46 in chloroform), 'y 173, 1710 cm. incarbon tetrachloride. Saponification of the foregoing 1713-acetoxycompound (0.5 g.) with potassium hydroxide (0.2 g.) in 80% aqueousmethanol (20 ml.) for /2 hour under reflux and purification from aqueousmethanol (70%) gave l7fi-hydroxy-2rx:4a-dimethylandrostan-3- one inflakes, M.P. 182 to 184 C., [ed +8 (c., 0.33 in chloroform), 11 3633,1708 emf in carbon tetrachloride.

Example 6 The process of Example 5 was repeated, propionic anhydridebeing substituted for acetic anhydride and the product being17,8-propio11oxy-2a:4a-dimethylandrostan- 3-one, needles from methanol,M.P. 142 to 143 C., vmax, 1735, 1713 cm." in carbon tetrachloride.

4 Example 7 6amethy1-4-phenylthiomethyltestosterone reacted with lithiumin liquid ammonia by the process of Example 1 gave17B-acetoxy-4u:6a-dimethylandrostan-3one, M.P. 160 to 163 C., [0:] 20(0., 0.54 in chloroform). Saponification of the foregoing acetoxycompound as in Example 5 gave l7 8-hydroxy-4az6a-dimethylandrostan-3-one, M.P. 224 to 225 C., 25.5 (c., 0.48 in chloroform).

17,6 propionoxy 4a:6-dimethylandrostan-3one, prepared in similar mannerto the 17-acetoxy compound, separated from aqueous methanol in flakes,M.P. 125 to 128 C., [041 -23 (c., 0.31 in chloroform).

Example 8 4-phenylthiomethyl-D-homotestosterone reacted with lithium inliquid ammonia by the process of Example 1 gave17,8acetoxy-4a-methyl-D-homoandrostan-3one.

Example 9 4-phenylthiomethyl-19-nortestosterone treated by the processof Example 1 (but omitting the final acetylation) gave 173-hydroxy-4a-methyl-l9-norandrostan-3-one (17,8-hydroxy-4-a-methyl-5a-oestran-3-one), needles from acetone/hexane (1:4),M.P. 160 to 161 C., [M +31 (0., 0.19 in chloroform).

Example 10 175 hydroxy 17amethyl-4-phenylthiomethylandrost- 4-en-3-one(2 g.) in pure tetrahydrofuran (100 ml.) was added to a stirred solutionof lithium (0.25 g.) in refiuxing liquid ammonia (250 ml.). Solidammonium chloride was added to discharge the blue colour, the ammoniawas allowed to evaporate, and water and chloroform were added. Thechloroform was washed, dried and evaporated, and the residue purifiedfrom aqueous methanol (70% hydroxy-14a:17a-dimethylandrostan-3one formedneedles, M.P. 154 to 156 C., 11 3480, 1702 cm. in liquid paraffin.

Example 11 4 phenylthiomethyl 25D spirost 4 en 3 one reacted withlithium in liquid ammonia by the process of Example 10, gave4a-methyl-5a:25D-spirostan-3-one, plates from acetone/hexane (1:4), M.P.216 to 218 C., 25 (c., 0.54 in chloroform).

Example 12 4 (p tolylthiomethyl) 25D spirost 4 en 3- one M.P. 164 to 166C., [0:1 +9 (c., 0.53 in chloroform), k 228 mp. (e=ll,745) and 254 my.(a =15,860) in ethanol, prepared according to the general procedure ofour co-pending application No. 852,971, now Patent No. 2,989,552, bycondensing 25D-spirost-4-en- 3-one, formaldehyde and toluene-p-thiol, inpresence of triethylamine as catalyst, and purified from ethanol wastreated by the process of Example 10, and gave 4a-methy1-5az25D-spirostan-3-one, plates from acetone/hexane (1:4), M.P. 216 to218 C., not depressed on admixture with the sample prepared according toExample 11.

Example 13 4 (n butylthiomethyl) testosterone was reacted with lithiumin liquid ammonia by the process of Example 1 and gave17fi-acetoxy-4a-methylandrostan-3one, M.P. 182 to 184 C.

Example 14 4-cyc1ohexylthiomethyltestosterone was reacted with lithiumin liquid ammonia by the process of Example 1 and gave17B-acetoxy-4a-methylandrostan-3-one, M.P. 182 to 184 C.

Example 15 4 (B hydroxyethylthiomethyl) testosterone was reacted wtihlithium in liquid ammonia by the process of Example 1 and gave17;3-acetoxy-4a-methylandrostan-3- one, M.P. 182 to 184 C.

Example 16 4-phenylthiomethylprogesterone (5 g.) in tetrahydrofuran (100ml.) was reduced with lithium (0.53 g.) in liquid ammonia (500 ml.) bytheprocess of Example 1. The product,20g-hydroxy-4u-methyl-5a-pregnan-3-one, separated from hexane in silkyneedles, M.P. 168 to 171 C., umax, 3410 and 1704 cm." in liquidparaffin.

The foregoing 20-hydroxy compound was dissolved in benzene (50 ml.) andstirred with a solution of chromium trioxide (5 g.) in water ml.) andacetic acid (30 ml.), with external cooling to 20 to 25 C., for 5 hours.The mixture was then diluted with water, and the benzene layer washedneutral, dried, and the solvent evaporated. Purification from acetonegave 4a-methyl5'a-pregnane 3:20-dione in silky needles, M.P. 195 to 196C., +97 (c., 0.69 in chloroform), v 1704 cm.- in CS A 283 m (e=69.4) inethanol.

Example 1 7 4 phenylthiomethylpregna 4:9(11) diene 3:20- dione, treatedby the process of Example 17, gave 40:- methyl 5a pregn 9(11) ene 3:20dione, u 1705 cm.- in liquid paraflin.

Example 18 4 phenylthiomethylandrost 4 ene 3:17 dione, treated by theprocess of Example 1, gave 17B-acetoxy- 4u-methylandrostan-3-one, M.P.177 to 179 C., identical with the sample obtained in Example 1.Oxidation of the crude reduction product with chromium trioxide as inExample 16 gave 4u-methylandrostane-3:17-dione, 11 1736, 1704 cm.- inliquid paraffin.

Example 19 160: methyl 4 phenylthiomethylprogesterone, treated by theprocess of Example 16, gave as the initial product 205 hydroxy 40x16dimethyl 51x pregnan 3- one, needles from hexane, M.P. 190* to 192 C., u3400, 1700 cm.- in liquid parafiin. Oxidation of this product by theprocess of Example 16 gave 4a2l6a-dimethyl-5a-pregnane-3:20-dione,prisms from hexane, M.P. 190 to 192 C., umax, 1700 emfin liquidparaffin.

Example 20 17a 20 20: 20: 21-bismethylenedioxy-4-phenylthiomethylpregn-4-ene-3: ll-dione, treated by the process of Example 10, gave11u-hydroxy17oa:20:20:20:2l-bismethylenedioxy-4a-methyl-5ot-pregnan-3-onewhich separated from chloroform/ ethanol (1:4) in needles, M.P. 261 to263 C., (decomp.), [a] 113 (c., 0.25 in chloroform), u 3450 and 1696cm.- in liquid paraflin.

The foregoing Ila-hydroxy compound (2.25 g.) in anhydrous pyridine (25'ml.) was treated with pyridine/ chromium trioxide complex prepared byadding chromium trioxide (2.5 g.) to pyridine (25 ml.). The mixture wasstirred for 24 hours, diluted with benzene, and filtered, and thefiltrate was washed with water, dilute sulphuric acid and water untilneutral, dried over sodium sulphate, stirred with decolourisingcharcoal, filtered, and the solvent evaporated. Purification of theproduct from chloroform/ethanol (1:4) gave 17u:20:20:21bismethylenedioxy 4a methyl 5a pregnane 3:11 dione in needles, M.P. 290to 292 C., (decomp.), -31 (c., 0.21 in chloroform).

Example 21 20:20 ethylenedioxy 17a hydroxy 4 (p tolylthiomethyl) pregn 4en 3 one (5 g.) [prepared by the process of our co-pending applicationNo. 852,- 971, now Patent No. 2,989,552, by condensing 20:20-ethylenedioxy 17oz hydroxypregn 4 en 3 one with toluene-p-thiol andformaldehyde in the presence of triethylamine as catalyst, and purifiedfrom aqueous methanol, M.P. 158 to 159 C., [cc] +73 (0., 1.18 inchloroform), X 227 m (e=1l,390) and 254.4 m (e =14,300)] in pure drytetrahydrofuran (100 ml.) was stirred at 40 C. and treated dropwise witha solution of lithium (l g.) in liquid ammonia (500 ml.) until a bluecolour persisted in the reaction mixture, when the addition was stoppedand sufiicient finely powdered ammonium chloride was added to dischargethe colour of the solution. The ammonia was allowed to evaporate and theresidue was treated with water and extracted with ether. Evaporation ofthe organic solvents gave a gummy residue which was purified bycrystallisation from aqueous methanol containing a drop of pyridine togive 20:20 ethylenedioxy 17oz hydroxy 40c methyl-5a-pregnan-3-one,felted needles, M.P. 223 to 225 C., -10 (c., 1.00 in chloroform), u3430, 1695 cm.- in liquid paraffin.

Removal of the protecting ethylenedioxy group by dissolving the compoundin aqueous acetic acid for 18 hours at room temperature, followed bypurification from aqueous methanol gave'17u-l1YClIOXY-4ot-Il'l6thYl-5ocpregnane-SzZO-dione, M.P. 262 to 267 C.,[a] 10 (c., 0.91 in chloroform), u 3470, 1700 0m. in liquid parafiin.

Example 22 The reduction process of Example 21 was repeated, and thecrude product remaining after evaporation of the organic solvents wastreated with acetic acid (60 ml.), acetic anhydride (15 ml.) andtoluenesp-sulphonic acid (1 g.) at room temperature for 18 hours. Themixture was then diluted with water (20 ml), and after a further 4 hoursmore water was added until solid material separated. Purification fromaqueous methanol gave '17a-acetoxy-4u-methyl-5a-pregnane-3:20-dione asflakes, M.P. 208 to 210 C., 1.5 (c., 0.96 in chloroform) .33; 1739 and1718 01117 Example 23 4-pheny1thiomethylergosta-4:7:22 trien '3 one wastreated by the process of Example 1, extra care being taken to ensurerigid exclusion of moisture. The product was 4a-methyl-5a-ergosta-722-dien-3 -one.

We claim:

1. A method for the preparation of 4a-methyl-3-oxo- Set-steroids whichcomprises reacting a 4-thiomethyl-3- oxo-A -steroid with a solution ofcompound selected from the group consisting of alkali and alkaline earthmetals in liquid ammonia.

2. A method as claimed in claim 1 wherein the alkali metal is lithium.

3. A method as claimed in claim 1 wherein a solution of the metal inliquid ammonia is brought into contact with a solution of the4-thiomethyl steroid in tetrahydrofuran.

4. 20 hydroxy 404116 dimethyl 5oz pregnan 3- I one M.P. to 192 C., u3400, 1700 cm.- in liquid References Cited in the file of this patentUNITED STATES PATENTS 2,844,602 Ringold et al. July 22, 1958 2,937,192Colton May 17, 1960 FOREIGN PATENTS 512,940 Great Britain Sept. 29, 1939686,135 Great Britain Jan. 21, 1953

1. A METHOD FOR THE PREPARATION OF 4A-METHYL-3-OXO5A-STEROIDS WHICHCOMPRISES REACTING A 4-THIOMETHYL-3OXO-$4-STEROID WITH A SOLUTION OFCOMPOUND SELECTED FROM THE GROUP CONSISTING OF ALKALI AND ALKALINE EARTHMETALS IN LIQUID AMMONIA.
 9. 20:20 - ETHYLENEDIOXY - 17A - HYDROXY -4A - METHYL5A-PREGNAN-3-ONE.